Senescence in the Cardiovascular System

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 24641

Special Issue Editor

Special Issue Information

Dear Colleagues,

Aging and senescence are related closely. Aging is the major risk factor for cardiovascular diseases and cardiovascular disease is the leading cause of death in the aged population. With the increase in life expectancy worldwide, the impact of cardiovascular diseases increases despite continuous progress in medicine. Senescence has been described more than 50 years ago in fibroblasts in culture and is characterized as irreversible cell cycle arrest independent of quiescence and terminal differentiation. More recent data suggest that cell senescence in a certain context in vivo might not be irreversible. This could provide additional opportunities to modify this cellular response to improve healthy aging. Traditionally, cardiovascular research related to senescence focused on the endothelium. Increasing evidence supports a much more complex interaction between endothelial cells, immune cells, smooth muscle, astrocytes in the blood–brain barrier, and adipocytes in cardiometabolic disorders. Further complexity is added by differences in endothelial function in distinct vascular beds. In general, vascular senescence is considered as detrimental while senescent liver endothelial cells fulfill important metabolic functions and are required for healthy ageing.

An additional important feature of senescence is the senescence-associated secretory phenotype (SASP). Detrimental effects are thought to be due to the release of this cocktail of secreted factors from senescent cells. However, recently established ablator and reporter mouse models suggest that senescent cells, SASP, and functions are different between P16INK4A and P21 expressing cell types questioning the concept of “the” senescent cell and “the SASP”.

All contributions shedding additional light and providing significant or provocative findings in the field of senescence in the cardiovascular system are welcome in this Special Issue of Cells.

Dr. Kay-Dietrich Wagner
Guest Editor

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Keywords

  • Senescence
  • endothelium
  • smooth muscle cells
  • pericyte
  • inflammation
  • senescence associated secretory phenotype
  • molecular markers
  • atherosclerosis
  • cardiometabolic disorders
  • tissue heterogeneity
  • progenitor cells
  • senolytics
  • senostatic

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Published Papers (6 papers)

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Research

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21 pages, 3197 KiB  
Article
Lipophilic Statins Eliminate Senescent Endothelial Cells by inducing Anoikis-Related Cell Death
by Barbora Belakova, Nicholas K. Wedige, Ezzat M. Awad, Simon Hess, André Oszwald, Marlene Fellner, Shafaat Y. Khan, Ulrike Resch, Markus Lipovac, Karel Šmejkal, Pavel Uhrin and Johannes M. Breuss
Cells 2023, 12(24), 2836; https://doi.org/10.3390/cells12242836 - 14 Dec 2023
Cited by 3 | Viewed by 2453
Abstract
Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of these cells has been shown to improve the health of aged experimental animals, leading to a clinical interest in finding [...] Read more.
Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of these cells has been shown to improve the health of aged experimental animals, leading to a clinical interest in finding compounds that selectively eliminate senescent cells while sparing non-senescent ones. In our study, we identified a senolytic capacity of statins, which are lipid-lowering drugs prescribed to patients at high risk of cardiovascular events. Using two different models of senescence in human vascular endothelial cells (HUVECs), we found that statins preferentially eliminated senescent cells, while leaving non-senescent cells unharmed. We observed that the senolytic effect of statins could be negated with the co-administration of mevalonic acid and that statins induced cell detachment leading to anoikis-like apoptosis, as evidenced by real-time visualization of caspase-3/7 activation. Our findings suggest that statins possess a senolytic property, possibly also contributing to their described beneficial cardiovascular effects. Further studies are needed to explore the potential of short-term, high-dose statin treatment as a candidate senolytic therapy. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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15 pages, 2075 KiB  
Article
The Use of Retinal Microvascular Function and Telomere Length in Age and Blood Pressure Prediction in Individuals with Low Cardiovascular Risk
by Hala Shokr, Victoria Lush, Irundika HK Dias, Anikó Ekárt, Gustavo De Moraes and Doina Gherghel
Cells 2022, 11(19), 3037; https://doi.org/10.3390/cells11193037 - 28 Sep 2022
Cited by 5 | Viewed by 1816
Abstract
Ageing represents a major risk factor for many pathologies that limit human lifespan, including cardiovascular diseases. Biological ageing is a good biomarker to assess early individual risk for CVD. However, finding good measurements of biological ageing is an ongoing quest. This study aims [...] Read more.
Ageing represents a major risk factor for many pathologies that limit human lifespan, including cardiovascular diseases. Biological ageing is a good biomarker to assess early individual risk for CVD. However, finding good measurements of biological ageing is an ongoing quest. This study aims to assess the use retinal microvascular function, separate or in combination with telomere length, as a predictor for age and systemic blood pressure in individuals with low cardiovascular risk. In all, 123 healthy participants with low cardiovascular risk were recruited and divided into three groups: group 1 (less than 30 years old), group 2 (31–50 years old) and group 3 (over 50 years old). Relative telomere length (RTL), parameters of retinal microvascular function, CVD circulatory markers and blood pressure (BP) were measured in all individuals. Symbolic regression- analysis was used to infer chronological age and systemic BP measurements using either RTL or a combination of RTL and parameters for retinal microvascular function. RTL decreased significantly with age (p = 0.010). There were also age-related differences between the study groups in retinal arterial time to maximum dilation (p = 0.005), maximum constriction (p = 0.007) and maximum constriction percentage (p = 0.010). In the youngest participants, the error between predicted versus actual values for the chronological age were smallest in the case of using both retinal vascular functions only (p = 0.039) or the combination of this parameter with RTL (p = 0.0045). Systolic BP was better predicted by RTL also only in younger individuals (p = 0.043). The assessment of retinal arterial vascular function is a better predictor than RTL for non-modifiable variables such as age, and only in younger individuals. In the same age group, RTL is better than microvascular function when inferring modifiable risk factors for CVDs. In older individuals, the accumulation of physiological and structural biological changes makes such predictions unreliable. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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Review

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14 pages, 1344 KiB  
Review
Statins in Chronic Kidney Disease—Effects on Atherosclerosis and Cellular Senescence
by Piotr Fularski, Julia Krzemińska, Natalia Lewandowska, Ewelina Młynarska, Maciej Saar, Magdalena Wronka, Jacek Rysz and Beata Franczyk
Cells 2023, 12(13), 1679; https://doi.org/10.3390/cells12131679 - 21 Jun 2023
Cited by 6 | Viewed by 2819
Abstract
Chronic kidney disease (CKD) is a serious health problem that can affect various systems in the human body. Renal failure promotes mechanisms of premature cellular aging and also features of generalized inflammation in the body, which translates into a close relationship between kidney [...] Read more.
Chronic kidney disease (CKD) is a serious health problem that can affect various systems in the human body. Renal failure promotes mechanisms of premature cellular aging and also features of generalized inflammation in the body, which translates into a close relationship between kidney dysfunction and cardiovascular disease (CVD). As kidney function deteriorates, cardiovascular risk and mortality increase in this group of patients. Oxidative stress and inflammation are two closely related processes that initiate a vicious cycle by activating each other. Together with aging, they represent the key factors that cause and exacerbate CVD in CKD. Patients with CKD are particularly vulnerable to the accumulation of aging endothelial cells, vascular smooth muscle and macrophages, increasing the risk of atherosclerosis. Several mechanisms are known that can lead to the progression of the aforementioned problems, such as the accumulation of uremic toxins, persistent inflammation, impaired lipid and electrolyte metabolism, nitric oxide (NO) deficiency, the increased production of reactive oxygen species (ROS) and damage to deoxyribonucleic acid (DNA) and mitochondria. According to research, we can distinguish a group of drugs that effectively counteract the negative effects of CKD—statins. This is a group of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and affect a number of cellular processes and pathways, resulting in the overall slowing of atherosclerosis and cellular aging. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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37 pages, 1641 KiB  
Review
Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
by Masayoshi Suda, Karl H. Paul, Tohru Minamino, Jordan D. Miller, Amir Lerman, Georgina M. Ellison-Hughes, Tamar Tchkonia and James L. Kirkland
Cells 2023, 12(9), 1296; https://doi.org/10.3390/cells12091296 - 2 May 2023
Cited by 32 | Viewed by 7702
Abstract
Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. Senescent cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many cardiovascular diseases. Therapies targeting senescent cells, especially senolytic drugs that selectively induce senescent [...] Read more.
Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. Senescent cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many cardiovascular diseases. Therapies targeting senescent cells, especially senolytic drugs that selectively induce senescent cell removal, have been shown to delay, prevent, alleviate, or treat multiple age-associated diseases in preclinical models. Some senolytic clinical trials have already been completed or are underway for a number of diseases and geriatric syndromes. Understanding how cellular senescence affects the various cell types in the cardiovascular system, such as endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells, progenitor cells, and cardiomyocytes, is important to facilitate translation of senotherapeutics into clinical interventions. This review highlights: (1) the characteristics of senescent cells and their involvement in cardiovascular diseases, focusing on the aforementioned cardiovascular cell types, (2) evidence about senolytic drugs and other senotherapeutics, and (3) the future path and clinical potential of senotherapeutics for cardiovascular diseases. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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22 pages, 905 KiB  
Review
Senescence-Associated Secretory Phenotype of Cardiovascular System Cells and Inflammaging: Perspectives of Peptide Regulation
by Vladimir Khavinson, Natalia Linkova, Anastasiia Dyatlova, Raisa Kantemirova and Kirill Kozlov
Cells 2023, 12(1), 106; https://doi.org/10.3390/cells12010106 - 27 Dec 2022
Cited by 13 | Viewed by 4223
Abstract
A senescence-associated secretory phenotype (SASP) and a mild inflammatory response characteristic of senescent cells (inflammaging) form the conditions for the development of cardiovascular diseases: atherosclerosis, coronary heart disease, and myocardial infarction. The purpose of the review is to analyze the pool of signaling [...] Read more.
A senescence-associated secretory phenotype (SASP) and a mild inflammatory response characteristic of senescent cells (inflammaging) form the conditions for the development of cardiovascular diseases: atherosclerosis, coronary heart disease, and myocardial infarction. The purpose of the review is to analyze the pool of signaling molecules that form SASP and inflammaging in cells of the cardiovascular system and to search for targets for the action of vasoprotective peptides. The SASP of cells of the cardiovascular system is characterized by a change in the synthesis of anti-proliferative proteins (p16, p19, p21, p38, p53), cytokines characteristic of inflammaging (IL-1α,β, IL-4, IL-6, IL-8, IL-18, TNFα, TGFβ1, NF-κB, MCP), matrix metalloproteinases, adhesion molecules, and sirtuins. It has been established that peptides are physiological regulators of body functions. Vasoprotective polypeptides (liraglutide, atrial natriuretic peptide, mimetics of relaxin, Ucn1, and adropin), KED tripeptide, and AEDR tetrapeptide regulate the synthesis of molecules involved in inflammaging and SASP-forming cells of the cardiovascular system. This indicates the prospects for the development of drugs based on peptides for the treatment of age-associated cardiovascular pathology. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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30 pages, 1609 KiB  
Review
Changes in Arterial Stiffness in Response to Various Types of Exercise Modalities: A Narrative Review on Physiological and Endothelial Senescence Perspectives
by Sandhya Kresnajati, Yi-Yuan Lin, Toby Mündel, Jeffrey R. Bernard, Hsin-Fu Lin and Yi-Hung Liao
Cells 2022, 11(22), 3544; https://doi.org/10.3390/cells11223544 - 9 Nov 2022
Cited by 13 | Viewed by 4209
Abstract
Arterial stiffness is a reliable independent predictor of cardiovascular events. Exercise training might enhance arterial compliance through improved metabolic health status. Different modes of exercise may have different effects on arterial stiffness. However, the interactions among different modes of exercise on endothelial senescence, [...] Read more.
Arterial stiffness is a reliable independent predictor of cardiovascular events. Exercise training might enhance arterial compliance through improved metabolic health status. Different modes of exercise may have different effects on arterial stiffness. However, the interactions among different modes of exercise on endothelial senescence, the development of arterial vascular stiffness, and the associated molecular mechanisms are not completely understood. In this narrative review, we evaluate the current evidence focusing on the effects of various exercise modes on arterial stiffness and vascular health, and the known underlying physiological mechanisms are discussed as well. Here, we discuss the most recent evidence of aerobic exercise, high-intensity interval training (HIIT), and resistance exercise (RE) on arterial stiffness and endothelial senescence in physiological and cellular studies. Indeed, aerobic, HIIT, and progression RE-induced arterial compliance may reduce arterial stiffness by effectively promoting nitric oxide (NO) bioavailability and reducing endothelial senescence. However, the transient increase in inflammation and sympathetic activation may contribute to the temporary elevation in arterial stiffness following whole-body high-intensity acute resistance exercise. Full article
(This article belongs to the Special Issue Senescence in the Cardiovascular System)
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